Prognostic significance of early vaso-occlusive complications in children with sickle cell anemia

QUINN et al. Significance of Early Vaso-Occlusive Complications

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Prognostic significance of early vaso-occlusive complications in children

with sickle cell anemia

Charles T. Quinn,1,2,3 Elizabeth P. Shull,2,3 Naveed Ahmad,3 Nancy J. Lee,2,3

Zora R. Rogers,1,2,3 and George R. Buchanan.1,2,3

From the 1Division of Hematology-Oncology, Department of Pediatrics, University

of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; 2Southwestern Comprehensive Sickle Cell Center, Dallas, TX, USA; and 3Children’s Medical Center Dallas, Dallas, TX, USA.

Supported partly by a grant from the National Institutes of Health (U54 HL 70588)

Charles T. Quinn, M.D.

U.T. Southwestern Medical Center

5323 Harry Hines Blvd.

Dallas, TX 75390-9063

Phone: 214-648-3896, Fax: 214-648-3122

Email: [email protected].

Abstract word count: 194

Body word count: 4,100

Short title: Significance of Early Vaso-Occlusive Complications

Keywords: sickle cell disease, risk factors, outcomes, vaso-occlusive crisis, acute

chest syndrome, dactylitis, children.

Statement of Authors’ Contributions: CTQ designed the research, oversaw the

data collection, assisted in the statistical analysis, and wrote the manuscript. EPS

and NJL collected and maintained the data. NA provided statistical services and

assistance writing the manuscript. ZR and GB provided project oversight,

feedback, and assistance writing the manuscript.

Blood First Edition Paper, prepublished online August 29, 2006; DOI 10.1182/blood-2006-02-005082

Copyright © 2006 American Society of Hematology

For personal use only.on August 25, 2016. by guest www.bloodjournal.orgFrom

http://www.bloodjournal.org/

http://www.bloodjournal.org/site/subscriptions/ToS.xhtml


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ABSTRACT

Sickle cell anemia (SS) is highly phenotypically variable, and early predictors of

outcome could guide clinical care. To determine whether early vaso-occlusive

complications predicted subsequent adverse outcomes in the Dallas Newborn

Cohort, we studied all members with SS or sickle-β0-thalassemia who presented

in their first year of life and had ≥5 years of follow-up. We defined three potential

early predictors: hospitalizations in the first 3 years of life for (1) painful events

other than dactylitis, (2) dactylitis, and (3) acute chest syndrome (ACS). We

studied the associations of these predictors with the following late adverse

outcomes (occurring after the third birthday): death; first overt stroke; use of

disease-modifying therapy; and hospitalizations for pain events and ACS. None

of the early events predicted death or stroke. Early pain and ACS both predicted

a modest, temporary increase in the number of later painful episodes, but early

ACS strongly increased the odds of more frequent ACS throughout childhood.

Dactylitis had limited utility as a predictor. Although we still lack a useful

prognostic framework for young children with SS, those who experience early

ACS might be candidates for higher risk interventions to mitigate or cure their

disease.





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INTRODUCTION

Homozygous sickle cell anemia (SS) is the most severe form of sickle cell

disease (SCD), but it is phenotypically variable, and the course of disease is

difficult to predict.1 Some individuals with SS have frequent vaso-occlusive

complications and die prematurely,2,3 while others have few problems and a

normal lifespan.4,5 Many genes both within and outside the beta globin locus

modify the phenotype of SS, but we have only a limited understanding of a few

such genotype-phenotype interactions.6,7

The prediction in very early childhood of later severe disease would permit risk-

based counseling for families and could justify the early use of disease-modifying

or curative interventions, such as hydroxyurea (HU), chronic transfusions (CT), or

stem cell transplantation (SCT). The hazards of these treatments vary greatly,

especially in comparison with preventive and supportive management alone.8

Accurate and reliable early predictors would provide the opportunity to better

balance the risks of these interventions with risks of the disease itself.

Vaso-occlusive complications have been studied as predictors of SCD severity.

Platt and colleagues reported for the Cooperative Study of Sickle Cell Disease

(CSSCD) that the rate of pain—itself a measure of clinical disease severity—

correlated with early mortality in adults.3 Likewise, Miller and colleagues for the

CSSCD showed that children who, in the first year of life, experienced dactylitis,

a painful vaso-occlusive complication of SCD, were more likely to have adverse

outcomes in later childhood, including death, stroke, frequent pain, and recurrent

ACS.9 This finding from the multi-center CSSCD infant cohort has not been





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confirmed in other cohorts. The prognostic significance of ACS and painful

episodes other than dactylitis in early childhood is not known.

We sought to test the assumption of many clinicians that children who

experienced vaso-occlusive complications in very early life, not limited to

dactylitis, were destined to have severe SCD in later childhood. To this end, we

studied the Dallas Newborn Cohort10 to determine if hospitalizations for painful

events, dactylitis, or ACS during the first three years of life were associated with

death, stroke, or other measures of severe disease between 3 and 20 years of

age. We hypothesized that hospitalizations for early vaso-occlusive

complications did not clearly predict later adverse outcomes.

PATIENTS AND METHODS

Cohort Members

This is a retrospective analysis of the Dallas Newborn Cohort,10 whose members

are tracked prospectively in our center’s comprehensive sickle cell disease

database. This newborn inception cohort includes the four common SCD

genotypes: SS, sickle-hemoglobin C disease (SC), sickle-β0-thalassemia (Sβ0),

and sickle-β+-thalassemia (Sβ+). It is unique among SCD cohorts because State

newborn screening for hemoglobinopathies identified all members, and all

subjects with SS or Sβ0 were prescribed prophylactic penicillin until at least 5

years of age. Accrual began in 1983 and is ongoing. The Cohort now includes

826 subjects and provides 7,275 patient-years of observation. This analysis

includes follow-up through July 13, 2005.





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We studied every member of the Cohort who was less than 20 years of age, who

had a diagnosis of either SS or Sβ0, whose first visit to our center was in the first

year of life, who were at least 5 years of age at the time of their last clinical

encounter in our center, and who had complete records available for review. The

percentage subjects who were lost-to-follow-up in the entire Cohort was 3.5%.10

We studied individuals with SS and Sβ0 as a single group because of the known

clinical similarity of the diseases, the very small number in the Sβ0 subgroup, and

the difficulty differentiating the two diseases using standard clinical and

laboratory assessments. The Institutional Review Board of UT Southwestern

approved the use of the clinical database for this project.

Early Predictors

We defined “early” vaso-occlusive complications to be those that occurred during

the first three years of life (before the third birthday). We defined this cut-off

before the data were collected and analyzed, and we chose it because pain

events other than dactylitis and ACS are uncommon in the first year of life.

Further, two additional years of “early” follow-up would provide a larger number

of early vaso-occlusive complications to study as predictors. This definition is

also clinically meaningful, because it permitted us to study early disease

manifestations before most irreversible organ damage, other than splenic

dysfunction, was likely to have occurred in most children.

We defined three potential “early” vaso-occlusive predictors: (1) hospitalization

for a painful episode (excluding dactylitis), (2) hospitalization for dactylitis, and (3)

hospitalization for ACS. These predictors were chosen because they are

common, clinically overt manifestations of SCD whose occurrence currently

informs clinical decision-making. We studied only inpatient episodes because of





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the design of our clinical database: we systematically track the discharge

diagnoses for all subjects’ hospitalizations but not outpatient painful events. Early

hospitalizations were identified by query of the database and review of selected

medical records, and they were categorized by the subject’s age at the time of

occurrence. Reasons for hospitalization (discharge diagnoses) had been

recorded at the time of each event. If the reason for any single hospitalization

was recorded in the database as both painful event and ACS (e.g., painful event

complicated by ACS), the hospitalization was counted as an episode of ACS only

(because ACS was considered to be the more severe complication). In our

clinical practice, we have defined ACS as an acute pulmonary illness in a person

who has SCD that is characterized by a new radiographic pulmonary infiltrate

and some combination of fever, hypoxemia, thoracic pain, and signs and

symptoms of respiratory illness.

Late Outcomes

We studied the associations of these early predictors with the following “late”

outcomes: (1) a death of any cause; (2) a clinically overt first stroke; (3) the use

of hydroxyurea (HU), chronic transfusions (CT), or stem cell transplantation

(SCT); (4) the number and rate of hospitalization for painful episodes; and (5) the

number and rate of hospitalization for ACS. By definition, all “late” outcomes

occurred on or after the third birthday. These outcomes were identified by query

of the database and review of selected medical records, and they were

categorized by the subject’s age at the time of occurrence. If the reason for any

single hospitalization was recorded as both painful event and ACS, the

hospitalization was counted as an episode of ACS only. Events up to age 20

years were included.





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To quantify late pain and ACS, we recorded all subjects’ hospitalizations for late

pain and ACS that occurred on or after the third birthday through the last clinical

encounter or the start date of a disease-modifying therapy (HU, CT, or SCT),

whichever occurred first. Only episodes of pain or ACS that occurred before the

start of any disease-modifying therapy (HU, CT or SCT) were included, because

such treatments are expected to alter the natural frequency of these events. The

use of a disease-modifying therapy was also studied as a surrogate measure of

disease severity.

For purposes of this study, we defined CT to be a program of regularly scheduled

red blood cell transfusions of at least 6 months’ duration given for the prevention

of complications of SCD. In our center, CT is used to prevent recurrent stroke

and, in select patients, to prevent frequent pain or recurrent ACS. At the time of

this analysis, we had not commonly used CT for primary stroke prevention. We

defined HU use as any administration of HU without regard to duration of

treatment or a subject’s adherence. HU is prescribed on an individual basis for

patients who have frequent pain or recurrent ACS, or when CT is not preferred

by the patient and family. To date, we have performed SCT only for prevention of

recurrent stroke.

Statistical Analysis

Bivariate Analysis. We compared the frequencies of the late categorical

outcomes (death, stroke, and use of disease-modifying therapy) between the

early predictor-positive and predictor-negative groups by two-sided Fisher’s exact

tests. For these bivariate analyses (predictor-outcome groupings), we studied the





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occurrence of early vaso-occlusive complications as binary variables (namely,

the occurrence or not of at least one complication). The predictive utility of

multiple early hospitalizations was tested in the multivariate analysis (see below).

For statistically significant associations, we calculated odds ratios (OR) with 95%

confidence intervals (95% CI).

We assessed differences in the occurrence of late pain and ACS between the

early predictor-positive and predictor-negative groups using means, mean

differences, and two-sided t-tests. To control for subjects’ different lengths of

follow-up, we classified each episode of pain and ACS by the subject’s age at the

time of its occurrence. Episodes were then categorized into non-overlapping 2-

year intervals defined by age of occurrence (3-4.99, 5-6.99, 7-8.99, 9-10.99, 11-

12.99, 13-14.99, 15-16.99, and 17-18.99 years of age). To additionally provide a

meaningful number of events for analysis these intervals were combined

cumulatively (3-6.99, 3-8.99, 3-10.99, 3-12.99, 3-14.99, 3-16.99, and 3-18.99

years of age), and the mean number of episodes of pain or ACS was calculated

in each interval. The pain and ACS episodes experienced by an individual were

included in one or more of these cumulative intervals only if he or she was alive

and evaluable in that interval.

For the bivariate analyses, P-values < 0.01 were considered statistically

significant to partially control for multiple comparisons.

Multivariate Analysis. We used binary logistic regression with backward model

building to predict late outcomes from early vaso-occlusive events. Here we

studied the number of early vaso-occlusive complications as a continuous

variable (to assess the contributions of multiple early events), unlike in bivariate





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analysis, wherein we considered only their occurrence or not. We included these

variables as predictors: early pain (excluding dactylitis), early dactylitis, early

ACS, sex, and genotype (SS or Sβ0). Logistic regression models were

constructed for the following outcomes: (1) death or stroke; (2) occurrence of late

painful episodes; (3) occurrence of late ACS; and (4) the composite occurrence

of late pain and ACS.

For each subject, we calculated rates of late pain and ACS that included all

events in the interval between the third birthday and the last clinical encounter, or

the start date of a disease-modifying therapy (HU, CT, or SCT), whichever

occurred first. Because the rates of late pain and ACS were not normally

distributed, and could not be normalized by transformation, multiple linear

regression was not tenable. Therefore, the rates of late pain and ACS were made

dichotomous for binary logistic regression in two different ways: (1) dichotomous

at the median rate for the whole sample (rate ≤ median vs. rate > median), and

(2) dichotomous at 1 episode/year (rate < 1 episode/year vs. ≥ 1 episode/year).

The cut-off of 1 episode/year was chosen in addition to the median because

some clinicians consider it to be a clinically meaningful threshold that denotes

disease severity. We calculated ORs and a 95% CIs for statistically significant

predictors in the model. We did not attempt to predict the late use of HU, CT, or

SCT, because bivariate analysis showed that CT and SCT were not associated

with early vaso-occlusive complications, and we believed that HU use was

largely a surrogate marker for late pain and ACS.

All data were analyzed using SPSS 13.0 statistical software (SPSS Inc.,

Chicago, IL, USA). Figures were generated using GraphPad Prism 4.0c

(GraphPad Software, San Diego, CA, USA).





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RESULTS

There were 264 subjects (55% male, 97% SS) in the analysis. The mean age at

first visit was 4.1 months [standard deviation (SD) 2.3 months], and the mean

length of follow-up was 12.1 years (SD 4.3 years). Twenty of 264 (7.6%) were

classified as lost to follow-up.

We found no statistically significant differences between males and females or

between SS and Sβ0 genotypes for any of the early or late events (data not

shown). All early and late events are reported in Table 1. Two subjects died of

pneumococcal sepsis (5 and 6 years of age), and one subject each died of acute

chest syndrome (5 years), complications of multiple strokes (7 years), and Down

syndrome with multiple congenital anomalies (5 years).

Bivariate Analysis

Associations of Early Events with Death and Stroke. We found that

hospitalization for pain, dactylitis, or ACS in the first three years of life did not

predict later death or clinically overt stroke (Table 2). Notably, none of the

subjects who had dactylitis later died or had a stroke. This superficially

“protective” effect of dactylitis was not statistically significant, so a true protective

effect should not be inferred. Because death and stroke were infrequent

outcomes, we also studied these two events as a single, composite outcome and

found, similarly, no associations with any of the early vaso-occlusive

complications.





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Associations of Early Events with Use of HU, CT, or SCT. We found that

early vaso-occlusive complications predicted only the later prescription of HU

(Table 2). The occurrence of early painful episodes gave an OR for later HU use

of 3.53 (95% CI 1.63, 7.64). Early ACS gave an OR for HU use of 5.69 (95% CI

2.55, 12.69). However, children who were hospitalized only for early dactylitis,

and not for pain or ACS, were not more likely to be treated with HU (P > 0.999;

Table 2). Early vaso-occlusive complications were not associated with later

initiation of CT. The single subject who underwent SCT to prevent recurrent

stroke was not hospitalized for pain, dactylitis, or ACS in the first three years of

life.

Associations of Early Events with Late Pain (Figure 1). We found that

subjects who were hospitalized for early painful episodes, compared to those

who were not, had a small increase in the mean number of late painful episodes

through approximately 11 years of age, but this effect was not seen in longer

periods of follow-up. Similarly, subjects who were hospitalized for early ACS had

a slightly higher mean number of late painful episodes through approximately 11

years of age, but not beyond. Dactylitis was not associated with more frequent

late pain considering periods of follow-up that were less than 18 years. However,

for the few subjects who had follow-up of 18 years or greater (N = 38), dactylitis

was associated with a statistically significantly increased number of late painful

episodes over the entire period of follow-up (Figure 1).

Associations of Early Events with Late ACS (Figure 2). There were no

associations between early pain or dactylitis and the mean number of late

episodes of ACS. However, children who were hospitalized for early ACS had an

increased mean number of late ACS episodes throughout all childhood. The





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mean difference was as high as 3.7 episodes of late ACS when comparing early

ACS-positive and ACS-negative subjects (Figure 2).

Multivariate Analysis

Death and Stroke. Neither alone nor in any combination did early pain, early

dactylitis, early ACS, sex, and genotype predict death and stroke. This was

consistent with the bivariate analyses.

Late Pain. Early VOC predicted the rate of late hospitalizations for pain if the cut-

off was set at the median rate for all subjects (≤0.071 vs. >0.071 episodes of

pain/year), but only 6% of the variability in late pain was explained by this model

(Table 3). If this cut-off was set instead at 1 episode/year, then early VOC was

not predictive, but early ACS was; however, this model explained only 5% of the

variability in late pain (Table 3). Early dactylitis, sex, and genotype were not

predictive of the occurrence of late pain. Thus, these models poorly predicted

late pain.

Late ACS. The only statistically significant predictor of the occurrence of late

ACS was early ACS itself, whether considering the cut-off rate at the median for

all subjects (≤0.1125 vs. >0.1125 episodes of ACS/year) or 1 episode/year

(Table 3). These models explained 15% and 24%, respectively, of the variability

in late ACS (Table 3). Early pain, early dactylitis, sex, and genotype did not

predict the occurrence of late ACS.

Late Pain and ACS. The only statistically significant predictor of the occurrence

of late pain and ACS (the composite outcome) was early ACS, whether





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considering the cut-off rate at the median (≤0.25 vs. >0.25 episodes of pain and

ACS/year) or 1 episode per year (Table 3). These models explained 15% and

12%, respectively, of the variability in late pain and ACS (Table 3). Early pain,

early dactylitis, sex, and genotype did not predict the occurrence of late pain and

ACS.

DISCUSSION

It is difficult to predict severe SCD during childhood, at least in part, because it is

difficult to define severe disease.1 Two objective indicators of disease severity

are death and stroke.3,11 Fortunately, both are becoming rare in children, given

the diminishing mortality from invasive bacterial infection and splenic

sequestration, as well as the prevention of first stroke using TCD to direct the

initiation of chronic red blood cell transfusions. Beyond these two objective

outcomes, investigators and clinicians have relied upon the enumeration of

hospitalizations for vaso-occlusive complications as an index of disease severity,

however imperfect. For example, the inclusion criteria for therapeutic clinical

trials typically require frequent painful episodes or recurrent ACS,12,13 but the

definitions of these events and the particular criteria used to denote severity are

not uniform. In the absence of good alternatives, we also studied these usual

measures of disease severity here, but we did not arbitrarily define a rate of pain

or ACS that was “severe”.

We showed that hospitalizations for vaso-occlusive complications during the first

three years of life did not predict the most objective markers of severe SCD:

death and stroke. The low incidence of death in the Dallas Newborn Cohort

reflects universal newborn screening and the uniform use of prophylactic





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penicillin. The CSSCD showed no association between overall pain rate and

stroke,11 and we found no increased risk of stroke from pain events that occur in

very early childhood. The incidence of stroke in the Cohort at the time of this

analysis, however, does not reflect the impact of primary stroke prevention,

because our center only recently instituted a TCD screening program.

Fortunately, death and stroke are becoming rare in children with SCD, so the

sickle cell community is now challenged to use other measures of severe

disease.

We studied the use of a disease-modifying therapy as a proxy for severe disease

and found that early vaso-occlusive complications predicted neither the later use

of CT nor SCT. This is not surprising, because stroke is the most common

indication for both CT and SCT. As such, neither stroke nor its proxies, CT and

SCT, was predicted by early vaso-occlusive complications. On the contrary, early

vaso-occlusive complications were associated with more frequent later use of

HU. Although this association is neither surprising nor wholly unexpected, it

should also be interpreted with caution because the decision to prescribe HU to

older children was likely biased by the knowledge that they had experienced

early complications. The imputation of disease-modifying therapy as a surrogate

marker of disease severity is also influenced by the varying prescribing practices

of physicians. Therefore, we also studied the frequency of late pain and ACS as

more direct, less biased indicators of disease severity.

We found that hospitalizations for pain or ACS in the first three years of life

predicted only a small and temporary increase in later painful events. Moreover,

the multivariate models could explain only a very small fraction of the variability in

late pain. It is unclear if such a modest increase in pain is clinically significant.





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Neither early dactylitis nor pain was associated with late ACS, but subjects who

had early ACS were more likely to have recurrent ACS throughout childhood.

Although factors other than early ACS, which are unknown, unmeasured, or both,

accounted for much of the variability in late ACS (Table 3), we infer a distinct

susceptibility to recurrent ACS. Perhaps ACS-related pulmonary injury

predisposes to subsequent ACS. An early study by Powars et al. suggested that

recurrent ACS caused chronic sickle cell lung disease.14 However, ACS in young

children tends to be mild,15 and recent studies indicate that neither pulmonary

hypertension16 nor steady-state oxyhemoglobin desaturation17 is associated with

prior ACS. Another interpretation is that the observed effect is due to asthma and

not ACS itself, but it is difficult to separate these two disease processes given the

definition of ACS as an acute pulmonary illness in an individual with SCD and

that bronchospasm and hypoventilation can precipitate ACS. So, asthma could

be the cause or consequence of ACS, or the two could share a common

pathophysiology. Indeed, Boyd and colleagues reported an association between

asthma and ACS,18 and Morris et al. found similar alterations of arginine

metabolism in both asthma and ACS.19,20

In the CSSCD infant cohort, the occurrence of dactylitis in the first year of life

conferred a relative risk of 2.6 for severe disease.9 Although our investigation

was not designed to refute or validate this particular CSSCD finding, which

included both inpatient and outpatient episodes of dactylitis, we found in contrast

that hospitalization for dactylitis in the first three years of life had limited

prognostic utility in the Dallas Newborn Cohort. Hospitalization for dactylitis did

not predict death, overt stroke, the use of a disease-modifying therapy, or later

ACS. Early dactylitis was also not associated with late pain, except in one

correlation with the 38 subjects who had 18 years or more of follow-up. This is an





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interesting observation that differs from the predictive pattern of early pain and

ACS for later pain events (Figure 1). Perhaps early dactylitis is associated with

an increase in late pain over a long period of follow-up, but the size of this sub-

group is small and the variability of this particular estimate of mean difference is

too high to justify strong inferences.

This retrospective analysis has a number of limitations. First, we studied only

hospitalizations for pain, dactylitis, and ACS. Many episodes of pain and

dactylitis are managed only at home and not in a hospital or an outpatient facility,

and we did not systematically record these outpatient events. Although many

factors unrelated to SCD, such as family situation and coping skills, determine

whether a patient is admitted to a hospital or not, generally the more severe

episodes are managed by hospitalization. Thus, we have studied the

associations among the relatively more severe of the early and late

manifestations of SCD. Second, the missing data of patients who were lost to

follow-up and censored at their last clinical encounter may have biased the

outcomes in either direction; however, there were not many lost subjects. Third,

there are numerous clinical, laboratory, and psychosocial factors that could

influence outcomes in SCD that we did not consider here. We could not

reasonably analyze so many predictors in a cohort of this size, however large.

Instead we chose a priori a small number of predictors and outcomes to test a

simple clinical question, and we realize that there may be confounding variables

that we have neither measured nor controlled for. Fourth, it is possible that

therapeutic improvements over the period of observation in this study could have

decreased the predictive nature of the early events, although such an effect

would probably be small given the mean follow-up of 12 years. Fifth, the use of

disease-modifying interventions in older individuals, which would decrease the





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frequency of late pain events, might partly account for the lack of association

between early events and late events after age 11 years. The overall rate of pain

in the study population increased after age 11 years and remained higher until 17

years (data not shown), so such confounding might be modest, but it cannot be

dismissed. Moreover, such a censoring effect is not apparent in dactylitis data.

Lastly, even though we nominally controlled for multiple comparisons, some of

the statistically significant associations we found may still have been type I

errors.

In summary, we have shown that ACS during the first three years of life predicts

recurrent ACS throughout childhood. A potential approach to reduce this risk may

be to screen for and aggressively manage any asthma-like disease in children

who have early ACS, and this strategy should be the focus of further research.

The prognostic significance of other early vaso-occlusive complications is quite

limited. Notably, none of the early events predicted the most objective

manifestations of severe SCD: death and stroke. Although a multitude of

predictors of outcome have been studied,1 we still lack a useful prognostic

framework for infants and young children with SCD. Until we are better at

prognostication, we should not endorse the use of a disease-modifying therapy in

very young children based solely on the occurrence of a few episodes of early

pain or dactylitis. Children who experience ACS in the first three years of life,

however, might be candidates for early, higher risk interventions to mitigate or

cure SCD.





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FIGURE LEGENDS

Figure 1. Associations between Early Predictors and Late Episodes of Pain.

Depicted here are the mean differences in the number of late painful episodes for

groups defined by the occurrence or not of each of the three early predictors

(whiskers are standard errors). Mean difference = (mean number of painful

episodes in predictor positive group) – (mean number of painful episodes in

predictor negative group). The mean differences are shown for cumulative,

overlapping intervals of follow-up beginning with the third birthday. (**P < 0.01;

***P < 0.001)

Figure 2. Associations between Early Predictors and Late Episodes of ACS.

Depicted here are the mean differences in the number of late episodes of ACS

for groups defined by the occurrence or not of each of the three early predictors

(whiskers are standard errors). Mean difference = (mean number of ACS

episodes in predictor positive group) – (mean number of ACS episodes in

predictor negative group). The mean differences are shown for cumulative,

overlapping intervals of follow-up beginning with the third birthday. (*P < 0.05; **P

< 0.01; ***P < 0.001)





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Table 1. Early Predictors and Late Outcomes.

Children who Experienced Events Early and Late Events Number of

Events Number Percenta

Early predictors

Painful eventsb 89 54 20.5

Dactylitis 18 16 6.1

ACS 151 86 32.6

Late outcomes

Death of any cause 5 5 1.9

First clinically overt stroke 30 30 11.4

Use of HU, CT or SCT 78 66 25

Painful events 642 130c 49.2c

Acute chest syndrome 410 150c 56.8c

aTotal N = 264 subjects bExcluding dactylitis cSubjects who experienced one or more events




QUINN et al. Significance of Early SCD Complications

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Table 2. Associations between Early Predictors and Late Death, Stroke, or the

Use of HU, CT, or SCT.

Occurrence of Early Predictors (Yes or No)

Frequency of Painful Episode Dactylitis ACS

Late Outcomes Yes No P Yes No P Yes No P

Death (%) 1.9 1.9 >0.999 0 2.2 >0.999 2.4 1.7 0.666

Stroke (%) 13.2 10.2 0.619 0 11.6 0.231 14.1 9.8 0.303

Death or Stroke (%) 13.2 12.1 0.817 0 13.2 0.233 15.3 11.6 0.43

HU (%) 26.4 9.2 0.002 12.5 12.4 >0.999 25.9 5.8 <0.001

CT (%) 17 14.1 0.663 6.3 15.3 0.48 20 12.7 0.141

SCT (%) 0 0.5 >0.999 0 0.4 >0.999 0 0.6 >0.999

The percentage of subjects who experienced each outcome is shown based on the

occurrence or not of each early predictor. P-values are calculated for each comparison

of percentages (yes vs. no) using Fisher’s exact test.





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Table 3. Summary of Predictive Variables in the Multivariate Models.

Late Rates Dichotomous at Median Number of Events/Year

Late Rates Dichotomous at 1 Event/Year Early Predictive Variables

P OR 95% CI R2

P OR 95% CI R2

For outcome: Late Pain Early pain (non-dactylitis) 0.002 1.93 1.26, 2.95 0.060 — — —

Early ACS — — — 0.009 1.57 1.12, 2.21 0.053

For outcome: Late ACS

Early ACS <0.001 2.23 1.52, 3.29 0.149 <0.001 2.51 1.67, 3.86 0.236

For outcome: Late Pain and ACS

Early ACS <0.001 1.92 1.36, 2.70 0.152 <0.001 1.93 1.42, 2.62 0.123

Odds ratios (ORs) are calculated by binary logistic regression analysis, which adjusts

for sex, genotype, early non-dactylitis pain, early dactylitis, and early ACS episodes as

appropriate. ORs correspond to a single unit increase in the predictive variable (an

episode of ACS or pain, where appropriate). Nagelkerke R2 values are reported as

coefficients of determination and indicate the proportion of variability in the outcomes

explained by the models.





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doi:10.1182/blood-2006-02-005082Prepublished online August 29, 2006;

BuchananCharles T Quinn, Elizabeth P Shull, Naveed Ahmad, Nancy J Lee, Zora R Rogers and George R with sickle cell anemiaPrognostic significance of early vaso-occlusive complications in children

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Prognostic significance of early vaso-occlusive complications in children with sickle cell anemia

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